Reduced notch activity is associated with an impaired marginal zone B cell development and function in Sly1 mutant mice.
MZ B cells represent a distinct lineage of naive B lymphocytes, apart from FO B cells and peritoneal B1 cells, and mediate humoral immune responses against blood-borne type 2 T-independent antigens. Regulation of MZ B cell development involves the Notch receptor signaling, the intensity of B cell receptor signals, and cell compartmentalization by adhesion and chemokine receptors. Our previous work showed that gene-targeted mice expressing a truncated form of the putative signaling adapter protein SLy1 exhibit reduced numbers of a splenic B cell population enriched in MZ B cells. Here, we demonstrate that Sly1(d/d) mice exhibit a partial, but selective, block in the transition from pre-MZ to mature MZ B cells. Development of both T1 and T2 precursor subsets and FO B cells was normal in Sly1(d/d) mice. Consistent with the loss of MZ B cells, the production of antigen-specific IgM antibodies following immunization with pneumococcal polysaccharides was severely impaired in Sly1(d/d) mice. Importantly, expression of the Notch signaling mediator RBP-J and the Notch target genes Hes-1 and Hes-5 was markedly reduced in MZ but not FO B cells of Sly1(d/d) mice. In contrast, B cell receptor signaling, expression and function of LFA-1 and alpha4-integrins, and expression of chemokine receptors appeared intact in Sly1(d/d) cells. Collectively, these results provide strong evidence that SLy1 is important for the generation and function of MZ B cells and suggest a novel link between SLy1 and the activity of the Notch pathway in the development of MZ B cells.
Scheikl
Tanja
T
Department of Surgery, TU Munich, Ismaninger Strasse 22, 81675 Munich, Germany.
Reis
Bernhard
B
Pfeffer
Klaus
K
Holzmann
Bernhard
B
Beer
Sandra
S
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D039441:Integrin alpha4 / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D000072056:Transcription Factor HES-1
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007075:Immunoglobulin M; D039441:Integrin alpha4; D016169:Lymphocyte Function-Associated Antigen-1; D011947:Receptors, Antigen, B-Cell; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C489685:Hes5 protein, mouse; C497571:Rbpj protein, mouse; C506091:SLY1 protein, mouse